The drug discovery landscape has been transformed by the genomics revolution. Advances in the understanding of biomolecular pathways and the roles they play in disease is generating vast numbers of targets for therapeutic intervention. Protein kinases now represent an extensive and important class of therapeutic targets.
Kinases are key components in almost all signal transduction pathways, modulating extracellular and intracellular signalling processes that mediate events such as cell growth and differentiation, metabolism and apoptosis. Kinases do this by catalysing the transfer of a phosphate group from ATP to protein substrates. The pivotal role of kinases is emphasized by the fact that kinases represent the third most populous domain in the proteome.
Kinases have been implicated in many diseases. Twenty percent of oncogenes code for tyrosine kinases. Kinases play pivotal roles in many leukemias, tumours and other proliferative disorders. Other states involving kinases include inflammatory disorders such as psoriasis, cardiovascular diseases such as restenosis, viral induced diseases such as Kaposi's sarcoma, circulatory diseases such as atherosclerosis and fibroproliferative diseases. Specific kinases are often implicated in particular disease states and therefore present themselves as potential targets for therapeutic intervention.
The kinase family includes serine/threonine kinases and tyrosine kinases, with the amino acid referring to the particular residue on a protein substrate that is phosphorylated. The tyrosine kinases can be further divided into receptor tyrosine kinases and non-receptor tyrosine kinases.
Considering the rate of generation and nature of the targets currently being deconvoluted by biologists, there is a need for the development of drug candidates, designed in a rational manner to purposely interact with selected targets, such as the kinases.
From a drug discovery perspective, carbohydrate pyranose and furanose rings and their derivatives are well suited as templates. Each sugar represents a three-dimensional scaffold to which a variety of substituents can be attached, usually via a scaffold hydroxyl group, although occasionally a scaffold carboxyl or amino group may be present for substitution. By varying the substituents, their relative position on the sugar scaffold, and the type of sugar to which the substituents are coupled, numerous highly diverse structures are obtainable. An important feature to note with carbohydrates, is that molecular diversity is achieved not only in the type of substituents, but also in the three dimensional presentation. The different stereoisomers of carbohydrates that occur naturally, offer the inherent structural advantage of providing alternative presentation of substituents. We have developed a system that allows the chemical synthesis of highly structurally and functionally diverse derivatised carbohydrate and tetrahydropyran structures, of both natural and unnatural origin. The diversity accessible is particularly augmented by the juxtaposition of both structural and functional aspects of the molecules.
A number of kinase inhibitors have appeared in the scientific literature to date. Many have entered human clinical trials and in two cases, Gleevac and Iressa, approval for the treatment of various tumours has been granted (Cohen, P., Nature Tev. Drug Discovery, 1, 309-316, 2002). The specificity of published kinase inhibitors varies widely and it is apparent from the study of Gleevac that specificity for a single kinase is not a prerequisite for the inhibitor becoming a useful drug, indeed the inhibition of more than one kinase may be an advantage for therapeutic intervention. Despite some promiscuity in the target kinase being acceptable, it is generally considered desirable to have good selectivity for the target kinase(s) over more general “housekeeping” kinases. Thus selectivity and inhibitor potency must be assessed on a case by case basis.
The level of inhibition in cell based assays also shows considerable variation from approximately 0.1 micromolar to over 100 micromolar as exemplified by the following table (a more detailed study can be found in: Davies et. al., Biochem. J., 351, 95-105, 2000; and Bain et. al., Biochem. J., 371, 199-204, 2003). It is frequently the case that the most potent inhibitor is not the most suitable inhibitor for therapeutic purposes.
Inhibitorcon-Top 5 kinases inhibitedcentrationkinase and residual activityML-9MSK-1ROCK-IISmMLCKS6K1CDK2100 μM14%23%25%27%38%LYPI3KCK2PHKGSK3βSGK294002 50 μM13%18%44%53%72%HA1077ROCK-IIPRK2MSK1S6K1PKA 20 μM 7%15%19%32%35%PP2LCKCDK2CK1SAPK2aMKK1 10 μM 1% 3%6%21%55%Ro-31-MAPKAPK1bMSK1PKCαGSK3βS6K18220 1 μM 2% 2% 3% 5% 6%MSK-1 = mitogen and stress activated protein kinase 1;ROCK-II = Rho associated coiled coil forming protein kinase II;SmMLCK = smooth myosin light chain kinase;S6K1 = p70 S6 kinase;CDK2 = cyclin dependant kinase 2;PI3K = phosphoinositide 3 kinase;CK2 = casein kinase 2;PHK = phosphorylase kinase;GSK3β = glycogen synthetase kinase 3β;SGK = serum and glucocortin induced kinase;PRK2 = PKC related kinase 2;PKA = protein kinase A;LCK = T cell specific kinase;CK1 = casien kinase 1;SAPK2a = p38 kinase;MKK1 = mitogen activated protein kinase 1;MAPKAP-K1b = mitogen activated protein kinase activated protein kinase 1b;PKCα = protein kinase C alpha.
It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in Australia or in any other country.